Breaching the blood-brain interface: Vasoactive neurons contact capillary vessels of the brain clock in the suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN) produces diffusible signals sufficient to sustain circadian locomotor rhythms, though the nature of such signals, their targets, and the pathway whereby such signals may travel is unknown. It is possible that the venous portal veins that connect the capillary beds of the SCN to those of the organum vasculosum of the lamina terminalis (OVLT) provide a vascular pathway whereby signals originating in SCN neurons can reach local targets in the OVLT. Given the presence of the blood-brain interface (BBI) within the SCN, it is unclear how diffusible signals originating in SCN neurons might access the capillary vasculature of this nucleus. Estimates of astrocyte coverage of capillary vasculature range widely, from 70-100%, and furthermore such coverage can change dynamically. In the present study, we investigated whether three vasoactive peptidergic processes found in the mouse SCN, namely vasopressin, vasoactive intestinal peptide and gastrin releasing peptide, might breach the BBI thereby accessing capillary vessels. Using widefield and confocal imaging, we found neuron-to-capillary contacts between varicosities bearing each of these vasoactive peptides and capillary basal membranes, pericytes and the endothelia in the mouse SCN of either sex. The findings suggest that all three vasoactive peptides may functionally breach the BBI of the SCN highlighting the importance of understanding how these peptides act on local vasculature to impact blood flow.<b>Significance Statement</b> The suprachiasmatic nucleus (SCN) produces diffusible signals sufficient to sustain circadian locomotor rhythms. The SCN - organum vasculosum lamina terminalis portal pathway provides a route whereby signals of SCN origin might be relayed to the rest of the brain. The presence of the blood-brain interface (BBI), however, raises the question of how diffusible signals of SCN origin might access the capillary vasculature of the nucleus. High resolution confocal imaging results suggest that varicosities of vasoactive peptides found in the SCN, namely vasopressin, vasoactive intestinal peptide and gastrin releasing peptide, breach the BBI and directly contact capillary vessels compartments including basal laminae, pericytes and endothelia.